Many of the medical devices used in contact with blood, tissue, skin, epithelial layers, wounds, cells in culture fluids, body fluids, dialysis fluids and/or therapeutic fluids for removal or infusion are made of materials which are not biocompatible. Thus in many systems the materials are creating untoward reactions in the context of application in the respective biological system. Different types of application are e.g. transcutaneous, in the peritoneal cavity, for access to the vascular system or in lines in which dialysis fluids are prepared.
Lack of biocompatibility may lead to blood clotting as well as inflammation and tissue activation and in addition, microbial infection can establish on the surface of devices. Colonization of bacteria and formation of biofilms on surfaces is a basic medical problem. Devices intended for long term contact, e. g. such as implanted stents, body fluid drainage systems or indwelling catheters can serve as a surface for host cell adhesion, permitting host cells to become activated, proliferate or to alter the normal physiological function and to restrict the function or intended use of a device. The formation of biofilms or bacteria colonisation on medical device surfaces creates a chronic inflammatory situation, which finally initiates failure of the device, and severe medical interventions or even life threatening situations.
The importance of antimicrobial activity and prevention of clot formation, e. g. in a catheter, has been disclosed in a paper by Wang et al, “Staphylococcus Epidermis Adhesion to Hydrophobic Biomedical Polymer is Medicated by Platelets”, J. of Infectious Diseases, 1993, 167:329-36, where a strong relation is described between platelets deposition and promotion of bacterial growth.
GB-1 041 058 discloses a composition and a method for protecting materials against attack by fungi or bacteria, wherein a bismuth compound is applied to a surface, e.g. by spraying or tipping, or is incorporated into the material which is to be protected during fabrication thereof. The bismuth compound is used in applications with textiles, paintings, and disinfectant or to protect plants against attack by fungi and other microorganisms.
In U.S. Pat. No. 5,928,671 is disclosed a series of bismuth salts having bactericidal and bacteriostatic activity for pharmacological use, antiseptic, antimicrobial and antibacterial agents for preventing infection and for disinfecting and cleaning surfaces, preservative and for killing biofilm organism and preventing the formation of biofilm. The composition is also used for treating bacterial infections of the gastro-intestinal tract.
A series of bismuth complexes, e. g. bismuth-propanedithiol or bismuth-pyrridione having antimicrobial and biofilm inhibition properties, have been described by Domenico et al, “The potential of bismuth-thiols for treatment and prevention of infection”, Infect. Med., 17(2):123-127, 2000. Said complexes are proposed to be used for coating of, e. g. indwelling catheters. Furthermore, Domenico et al have discussed the “Activities of bismuth thiols against Staphylococci and Staphylococcal biofilms”, Antimicrobial Agents and Chemotherapy, May 2001, p. 1417-1421.
WO 00/21585 discloses polycaprolactone, PDMS, as part of a polymeric film by the addition of a further component exerting antimicrobial activity and keeping the high biocompatibility profile of the coating (no cytotoxicity, improved thrombogenicity and reduced promotion of bacterial growth).
U.S. Pat. No. 6,267,782 relates to a mixture of a metal composition and a biocompatible material in a solution for the preparation of a medical article comprising antimicrobial metal. The biocompatible material may comprise a biological polymer and the metal may be a bismuth composition. However, the metal composition is deposited on the surface of the article, resulting in release of bismuth from the article.
Prevention of blood access derived infections, e. g. in catheters is of great importance in public health perspectives, i. e. increasing resistance of bacteria against antibiotic strategies and with respect to costs related to subsequent medical treatment after bloodstream infections and septic complications. For example, intravascular catheter related bloodstream infections are an important cause of illness and excessive medical costs. Many catheter related bloodstream infections occur in intensive care units at the price of many deaths and high cost.
Therefore a lot of strategies have been developed to prevent these complications. As described by Donlan et al, “Biofilms and Device-associated Infections, Emerging Infectious Diseases, 89, Vol. 7, No. 2, March-April, 2001, most of these strategies to impregnate polymeric materials, e g by silver or other additives or even antibiotics, result in an ineffective control of bacteria growth and biofilm formation.
It is described by Mermel et al, “New Technologies to Prevent Intravascular Catheter Related Bloodstream Infections”, Emerging Infectious Diseases, Vol. 7, No. 2, March-April, 2001, that technological interventions by impregnating catheter materials with different kinds of bacterial agents is not effective. In vitro studies have suggested the potential for bacterial resistance against the antimicrobial agents used to impregnate these catheters as their clinical use becomes more widespread. In addition to these very often non-technological inventions such as nurse training and use of sterile environment by sterile masks, sterile clothes, etc helps to reduce catheter related infections.
However, there is no technical solution available at the moment preventing, at the catheter site, the formation of biofilms by bacterial adhesion and proliferation. From pharmaceutical textbook knowledge, many bismuth compounds are used in medical and/or pharmaceutical practice e g bismuth carbonate, bismuth-nitrate, bismuth-citrate, bismuth-salicylate. Related drug formulations are known as Angass-S-Ulcowics, Bismoflk-V, Jadrox-600, Ulcolind, etc. Bismuth salts and thiols are active against a broad spectrum of bacteria. The inhibitory concentration is in the range of 3 to 300 μmol bismuth-3+. Most of the known bacteria strains are susceptible to bismuth compounds and it is of importance to note that they are most effective against Staphylococcus Aureus including methicillin resistant Staph. aureus (MRSA) (Dominico et al).
The main problem is that bismuth compounds, especially bismuth thiols are potentially toxic. The mechanism how bismuth is working to prevent bacterial proliferation is not completely clear. It was recently shown that Bis-BAL could enhance phagocytotic uptake of bacteria by neutrophils. Furthermore it has been shown that this compound could significantly enhance complement binding to cells and by this accelerate opsonisation and phagocytosis. However, this mechanism cannot be applied to prevent bacterial growth in aqueous solution. Therefore, a specific effect of bismuth must act on bacteria proliferation. It has been proposed that bismuth inactivates respiratory enzymes in the cytoplasma and by this leads to inhibition of capsular polysaccharide expression in bacteria. These polysaccharides are necessary to form a gel like autolayer surrounding the bacteria and preventing the action of antibiotic. Furthermore, it is advantageous that bismuth does not destroy the bacterial cell membrane and by this prevents the release of endotoxins which are known as an important stimulator of the immune system, especially in dialysis patients or patients depending on extracorporeal treatment during intensive care therapies.
Based on these findings, there is a clear medical need to design materials or surfaces in medical devices, especially in catheters, access devices or port systems, which prevent bacterial growth and subsequent biofilm formation and prevent bioincompatible reactions, especially formation of clots and fibrin or platelets deposits. To produce medical devices resistant to infections, a potent antimicrobial efficiency combined with an excellent biocompatibility over time is needed.